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Use of Umbilical Core Blood derived HSC to Treat Acute Kidney Injury

使用脐带血造血干细胞治疗急性肾损伤

基本信息

批准号：
7936898
负责人：
FANGMING LIN
金额：
$ 30.72万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936898
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Aorta Area Autologous Blood Blood Banks Bone Marrow CD34 gene Cell Separation Cell Therapy Cells Chronic Kidney Failure Clinical Cost of Illness Dedications Developmental Gene End stage renal failure Ensure Epigenetic Process Epithelial Epithelial Cells Ethics Expenditure Goals Gonadal structure Hematopoiesis Hematopoietic Hematopoietic stem cells Histone Deacetylase Histone Deacetylase Inhibitor Hospitals Human Immunodeficient Mouse Immunosuppression In Vitro Incidence Infant Injection of therapeutic agent Injury Kidney Kidney Diseases Lead Measures Medicare Mesenchymal Mesonephric structure Monitor Morbidity - disease rate Mus Natural regeneration Phenotype Quality of life Recovery Recovery of Function Regenerative Medicine Reperfusion Injury Risk Safety Site Stem cells Structure Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Tissues Translating Translations Transplantation Trichostatin A Tubular formation Umbilical Cord Blood clinical application cytokine effective therapy experience improved innovation kidney cell mortality mouse model paracrine programs public health relevance repaired small molecule stem stem cell biology

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to take an innovative approach to develop cell therapeutic agents from human umbilical cord blood-derived hematopoietic stem cells (UCB-HSC) to treat acute kidney injury (AKI). Acute kidney injury not only has a high morbidity and mortality rate but often leads to chronic kidney disease. At the present time, there is no specific treatment for AKI. Once the kidney fails, treatment of chronic kidney disease costs 20% Medicare expenditure. New and more effective treatments, such as stem cell-based therapy, will have significant clinical and financial impact. We have shown that mouse bone marrow HSC can be reprogrammed into cells expressing renal developmental genes after 1 week of treatment with cytokines and nephrogenic factors in vitro. Further treatment of the cells with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances reprogramming from 6% to 38%. Injection of the reprogrammed cells into mice with renal ischemic injury accelerates kidney structural and functional recovery. To begin to translate these findings clinically, we propose to reprogram human UCB- HSC and test their therapeutic effect in mouse models of AKI. Umbilical cord blood contains higher concentrations of CD34+ stem and progenitor cells. The cells can be isolated easily without risk to the donors. The UTSW-affiliated Parkland Memorial Hospital delivers about 47 infants a day, which ensures an abundant supply for cell isolation. Using a similar approach for the mouse bone marrow HSC, CD34+ cells from human umbilical cord blood will be treated in vitro with cytokines, nephrogenic factors and a HDAC inhibitor TSA to induce hematopoietic-to-renal conversion. The induced cells will be characterized for the expression of a panel of renal developmental genes, and their ability to differentiate into epithelial cells and form tubular structures (Aim 1). Furthermore, the induced cells will be transplanted into mice with acute ischemia-reperfusion injury to test whether they accelerate renal functional and structural recovery. The mechanisms of renal protection by direct cell replacement into the repairing tubules and/or paracrine effect to decrease epithelial and endothelial injury and increase intrinsic renal cell regeneration will be investigated (Aim 2). This project may represent the first step toward translation of stem cell biology to the bedside. We are confident that with our experience and dedication, we will be able to complete the studies in Aim 1 in the first 9 months and the studies in Aim 2 in the next 15 months. PUBLIC HEALTH RELEVANCE: Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at the present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop cell therapeutic agents from human umbilical cord blood-derived stem cells to treat acute kidney injury.

项目描述（由申请人提供）：该项目的总体目标是采用创新的方法从人脐带血来源的造血干细胞（UCB-HSC）中开发细胞治疗剂来治疗急性肾损伤（AKI）。急性肾损伤不仅具有很高的发病率和死亡率，而且往往导致慢性肾脏疾病。目前，还没有针对AKI的特异性治疗方法。一旦肾脏衰竭，慢性肾脏疾病的治疗费用占医保支出的20%。新的和更有效的治疗方法，如基于干细胞的治疗，将产生重大的临床和财政影响。我们已经证明，在体外用细胞因子和肾源性因子处理1周后，小鼠骨髓HSC可以被重编程为表达肾脏发育基因的细胞。用组蛋白去乙酰化酶（HDAC）抑制剂trichostatin a （TSA）进一步处理细胞，可将重编程从6%提高到38%。将重组细胞注射到肾缺血性损伤小鼠体内，可加速肾脏结构和功能的恢复。为了开始将这些发现转化为临床，我们建议对人UCB- HSC进行重编程，并在小鼠AKI模型中测试其治疗效果。脐带血含有高浓度的CD34+干细胞和祖细胞。这些细胞可以很容易地分离出来，对供体没有风险。utsw附属的帕克兰纪念医院每天接生约47名婴儿，这确保了细胞分离的充足供应。采用类似的方法对小鼠骨髓HSC，将在体外用细胞因子、肾源性因子和HDAC抑制剂TSA处理来自人脐带血的CD34+细胞，以诱导造血向肾转化。这些诱导细胞的特征是表达一组肾脏发育基因，以及它们分化为上皮细胞和形成管状结构的能力（目的1）。进一步，将诱导的细胞移植到急性缺血再灌注损伤小鼠体内，观察其是否能促进肾脏功能和结构的恢复。将研究通过直接细胞替代进入修复小管和/或旁分泌作用来减少上皮和内皮损伤并增加内在肾细胞再生的肾保护机制（目的2）。这个项目可能代表着干细胞生物学应用于临床的第一步。我们相信，凭借我们的经验和努力，我们将能够在前9个月内完成Aim 1的研究，并在接下来的15个月内完成Aim 2的研究。